4-(3-Isopropylamino-2-hydroxypropoxy indene

ABSTRACT

Novel indene derivatives represented by the general formula ##STR1## wherein R represents lower alkyl, phenylloweralkyl or lower cycloalkyl, and acid addition salts thereof useful as β-receptor antagonists.

This application is a continuation of Ser. No. 141,936, filed May 10,1971, now abandoned which in turn is a continuation-in-part of Ser. No.876,070, filed Nov. 12, 1969, now abandoned.

This invention relates to novel indene derivatives having valuabletherapeutic properties, non-toxic salts thereof, and to processes fortheir production.

The therapeutically active compounds of this invention are representedby the general formula ##STR2## wherein R represents a lower alkyl,phenylloweralkyl or lower cycloalkyl group.

The term "lower alkyl" as used herein means both straight and branchedchain aliphatic hydrocarbon groups such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl, etc. The term"phenylloweralkyl", which may contain more than one phenyl group, isrepresented by groups such as benzyl, diphenylmethyl, β-phenylisopropyl,etc. The term "lower cycloalkyl" is represented by groups such ascyclopentyl and cyclohexyl, etc.

The compounds I of the present invention can be prepared by reacting acompound of the general formula ##STR3## wherein A represents a hydrogenatom or a 2,3-epoxypropyl group with an amine of the general formula

    B-NH-R                                                     (III)

wherein R is defined as above and B represents a3-halogeno-2-hydroxypropyl group when A is a hydrogen atom; and when Ais a 2,3-epoxypropyl group, B is a hydrogen atom.

Thus, according to one embodiment of the process of this invention, thenovel compounds I are prepared by condensing a 4-hydroxyindenerepresented by the formula ##STR4## with a1-halogeno-2-hydroxy-3-loweralkylaminopropane of the general formula

    X--CH.sub.2 CH(OH)CH.sub.2 NH--R                           (V)

wherein X represents a halogen atom and R is defined as above.

The reaction is preferably carried out in the presence of anacid-binding agent, preferably an alkali metal or derivative thereof,e.g. a hydroxide, a hydride, an amide, an alcoholate or a metal-alkylcompound.

The reaction is also preferably carried out in the presence of an inertsolvent, such as water, methanol, ethanol and the like, at roomtemperature or at an elevated temperature, e.g. up to the refluxtemperature of the solvent.

The novel compounds I of this invention can also be obtained by thecondensation of 4-(2,3-epoxypropoxy)indene of the structural formula##STR5## with a lower alkyl amine of the general formula

    H.sub.2 N-R                                                (VII)

wherein R is defined as above.

The reaction of this latter method is carried out in the presence orabsence of a suitable inert organic solvent, for example, methanol,ethanol, ether, ethyl acetate and the like at room temperature or at anelevated temperature, e.g. up to the reflux temperature of the solvent.

The 4-(2,3-epoxypropoxy)indene VI employed as a starting material in theabove-mentioned process may be prepared by reacting 4-hydroxyindene IVwith 1,2-epoxy-3-halogenopropane.

The 4-hydroxyindene IV in solution in a solvent such as water or anorganic diluent is isomerized by a basic substance to form7-hydroxyindene.

Therefore, the compounds I of the present invention contain an isomer,that is 7-(3-loweralkylamino-2-hydroxypropoxy)-indene represented by thegeneral formula ##STR6## wherein R is as defined above.

The novel compounds I of this invention, of course, contain anasymmetric carbon atom at the 2-position in its side chain and can existas a d- or l-isomer or a racemate.

From the compounds I of this invention, the substantially non-toxic,i.e. pharmaceutically acceptable, acid addition salts can be prepared inthe usual manner with pharmaceutically non-toxic inorganic or organicacids, such as hydrochloric acid, sulfuric acids, nitric acid,phosphoric acid, formic acid and acetic acid.

The compounds I of this invention possess valuable therapeuticproperties which render them useful as adrenergic β-receptor blockingagents. (Experiments 1 and 3)

What should be noted as a distinctly meritorious property of thecompounds I of this invention is that they improve the cardiac function,while known adrenergic β-receptor antagonists, such as4-(3-isopropylamino-2-hydroxypropoxy)indane have deleterious effects onthe cardiac function. (Experiment 2)

Accordingly, the products I of this invention are useful as adrenergicβ-receptor antagonists which can be administered to patients (humans)without the apprehension of damaging the heart.

The compounds I of the present invention are effective when orallyadministered. Clinically they may be administered orally at a dailydosage of about 5-15 mg., e.g. 10 mg., of the compounds, optionally individed portions. They may also be administered intramuscularly orintravenously to provide a total daily dosage of about 2-5 mg., e.g. 4mg., of the compounds, optionally in divided portions. The compounds Imay be administered in combination with a pharmaceutically acceptablecarrier, e.g. cellulose, starch or talc, or a combination thereof.

The invention will be described in further detail in the followingexamples which are presented by way of illustration only and not aslimiting the scope of the invention.

EXAMPLE I

a. A mixture of 0.9 g. of 4-hydroxyindene, 2.0 g. of1,2-epoxy-3-chloropropane, 2.7 g. of potassium carbonate and 15 ml. ofacetone was refluxed at about 57° C. for 24 hours. Acetone was removedby vacuum distillation, the residue was washed with 10 ml. of water andthen extracted with 20 ml. of ether three times. The ether extract wasdried with magnesium sulfate, filtered and subjected to columnchromatography using a column (having an inside diameter of about 3 cm.and a height of about 50 cm.) packed with silica gel. The 5th to 7thfractions (volume of one fraction is 50 ml.) recovered from thechromatographic column using chloroform as the effluent were combinedtogether and concentrated to provide 0.6 g. of4-(2,3-epoxypropoxy)indene.

b. A mixture of 0.42 g. of 4-(2,3-epoxypropoxy)indene, 1.20 g. ofisopropylamine and 20 ml. of methanol was stirred in a flask at roomtemperature for 2 hours. Methanol and unchanged isopropylamine wereremoved by vacuum distillation and the residue was recrystallized from amixture of n-hexane and ether to yield 0.41 g. of4-(3-isopropylamino-2-hydroxypropoxy)indene having a melting point of88°-89° C.

c. To a solution of 0.41 g. of4-(3-isopropylamino-2-hydroxypropoxy)indene in 80 ml. of absolute etherthere was added dropwise a hydrochloric acid-ether mixture at 0° C. withstirring. The precipitates thus formed were recovered by filtration andrecrystallized from a mixture of ethanol and ether to provide 0.44 g. ofthe hydrochloride of 4-(3-isopropylamino-2-hydroxypropoxy)indene. M.P.147°-148° C.

    Elementary analysis as C.sub.15 H.sub.22 NO.sub.2 Cl:                                      C (%)   H (%)     N (%)                                          ______________________________________                                        Calculated:    63.48     7.81      4.94                                       Found          63.52     7.86      4.96                                       ______________________________________                                    

With respect to adrenergic β-receptor blocking action,4-(3-isopropylamino-2-hydroxypropoxy)indene obtained in Example 1 and4-(3-isopropylamino-2-hydroxypropoxy)indane were tested according toExperiment 1.

EXPERIMENT 1

The atria obtained from a male Hartley guinea pig weighing 300-500 g.were trimmed and placed in chambers containing Tyrode solutionoxygenated with 95% oxygen and 5% carbon dioxide and maintained at 30°C.

Contractile force was recorded by an isometric lever connected to astrain gauge tension transducer. Antagonistic activity of the testeddrugs on the 1-isoproterenol-induced increase of the atrial contractionwas investigated.

The first control response was measured adding 1-isoproterenol to thebath fluid to a final concentration of 5 × 10⁻⁸ g./ml. Then thepreparation was washed and the same procedure was repeated afterapplication of the drugs to be tested, i.e.4-(3-isopropylamino-2-hydroxypropoxy)indene and4-(3-isopropylamino-2-hydroxypropoxy)indane (final concentrations of 8 ×10⁻⁹ g./ml. and 5 × 10⁻⁸ g./ml.), 10 minutes previously. The results areindicated in Table 1.

                  Table 1                                                         ______________________________________                                                                      Inhibition                                      Compound tested Dose (g./ml.) rate (%)                                        ______________________________________                                        4-(3-isopropylamino-2-                                                                        8 × 10.sup.-9                                                                         30.7                                            hydroxypropoxy)indene                                                                         5 × 10.sup.-8                                                                         81.5                                            4-(3-isopropylamino-2-                                                                        8 × 10.sup.-9                                                                         30.4                                            hydroxypropoxy)indane                                                                         5 × 10.sup.-8                                                                         88.4                                            ______________________________________                                    

Direct effects of these same compounds on a heart devoid of autonomousnervous control were investigated according to Experiment 2.

EXPERIMENT 2

The studies were performed on Wistar rats weighing 250-350 g.anesthetized with pentobarbital (50 mg./kg., i.p.) 18 - 24 hours aftertreatment with reserpine (8 mg./kg., s.c.). Both adrenal glands wereremoved and bilateral vagotomy in the neck was performed. One ml./kg. of4-(3-isopropylamino-2-hydroxypropoxy)indene or4-(3-isopropylamino-2-hydroxypropoxy)indane was injected intravenouslyover three minutes in a single dose varying from 0.01 to 0.1 mg./kg. andthe heart rate was recorded by a cardiotachometer of Nihon Koden Co. (RM100). The results are indicated in Table 2. In Table 2, the symbol +represents an increase in heart rate, while the symbol - represents adecrease in heart rate. The standard error is shown in parenthesis.

                                      Table 2                                     __________________________________________________________________________           Number     Change of heart rate (%)                                    Compound                                                                             of   Dose  1 minute                                                                           5 minutes                                                                           15 minutes                                                                           30 minutes                                tested animals                                                                            (mg./kg.)                                                                           after                                                                              after after  after                                     __________________________________________________________________________                      +2.4 +3.8  +3.2   +1.7                                      4-(3-iso-                                                                            2    0.01  (±) 0.9                                                                         (±0.2)                                                                           (±0.1)                                                                            (±0.2                                  propylamino-                                                                  2-hydroxy-        +5.6 +8.4  +8.7   +5.2                                      propoxy)-                                                                            4    0.05  (±2.1)                                                                          (±3.4)                                                                           (±4.0)                                                                            (±3.1)                                 indene            +1.5 +4.1  +3.5   +4.0                                             3    0.10  (±0.4)                                                                          (±1.2)                                                                           (±1.4)                                                                            (±2.0                                                    -0.9 +0.3  -1.9   -1.7                                      4-(3-iso-                                                                            3    0.01  (±0.1)                                                                          (±0.8)                                                                           (±0.9)                                                                            (±0.3)                                 propylamino-      -2.1 -2.0  -2.0   -4.6                                      2-hydroxy-                                                                           4    0.05  (±0.5)                                                                          (±0.5)                                                                           (±0.9)                                                                            (±1.4)                                 propoxy)-         -5.9 -8.7  -8.7   -5.4                                      indane 2    0.10  (±1.4)                                                                          (±0.3)                                                                           (±0.3)                                                                            (±0.6)                                 __________________________________________________________________________

When 4-(3-isopropylamino-2-hydroxypropoxy)indene is injectedintravenously to white mice, the LD₅₀ value is 25 mg./kg.

EXPERIMENT 3

The effects of certain compounds on isoproterenol-induced tachycardia aswell as on resting heart rate were studied in reserpinized, vagotomizedrats. The rat was anaesthetized with pentobarbital 18 hours aftertreatment with reserpine (8 mg./kg., i.p.) and vagotomized bilaterallyin the neck. Heart rate was recorded by a cardiotacho-meter (RT-2,Nihonkoden). After the control response to l-isoproterenol (0.1 μg./kg.,i.v.) was obtained, each compound tested was injected intravenously insuch doses that the cumulative dose increased four-fold: 0.01 - 0.04 -0.16 - 0.64 - 2.56 mg./kg., at 20 minute intervals. Ten minutes aftereach dose of the compound an intravenous injection of l-isoproterenol(0.1 μg./kg.) was administered and the increase in heart rate wasrecorded. The dose producing 50% blockade of the positive chronotropiccontrol response to l-isoproterenol (ED-50) was estimated in eachexperiment from curves obtained by plotting inhibition percentageagainst log cumulative dose. The results are indicated in Table 3, inwhich the standard error is provided by the ± designation.

                                      Table 3                                     __________________________________________________________________________              Number                                                              Compound  of              Dose of compound (mg/kg, i.v.)                      tested    animals   Control                                                                             0.01  0.04  0.16  0.64  2.56 ED50                   __________________________________________________________________________                                                           (mg/kg)                saline    2    BHR.sup.a)                                                                         210, 295                                                                            205, 295                                                                            210, 290                                                                            215, 285                                                                            210, 290                                                                            --                                         Res.sup.b)                                                                         100, 100                                                                            106, 94                                                                             102, 100                                                                            108, 105                                                                            102, 103                                                                            --   --                     4-(3-isopropyl-                                                                         6    BHR  232 ± 6                                                                          235 ± 12                                                                         246 ± 13                                                                         245 ± 14                                                                         245 ± 12                                                                         --                          amino-2-hydroxy-                                                                             Res  100    74 ± 3                                                                           50 ± 2                                                                           23 ± 2                                                                           5 ± 1                                                                           --   0.039 ± 0.002       propoxy)indene                                                                4-(3-sec-butyl-                                                                         4    BHR  218 ± 6                                                                          220 ± 13                                                                         225 ± 14                                                                         236 ± 16                                                                         228 ± 23                       amino-2-hydroxy-                                                                             Res  100    81 ± 4                                                                           65 ± 1                                                                           40 ± 5                                                                           17 ± 3                                                                           6± 1                                                                           0.088 ± 0.011       propoxy)indane                                                                4-(3-isopropyl-                                                                         3    BHR  265 ± 15 245 ± 15                                                                         236 ±  14                                                                        238 ± 17                                                                         --                          amino-2-hydroxy-                                                                             Res  100          54 ± 5                                                                           33 ± 14                                                                          12 ± 1                                                                          --   0.065 ± 0.013       propoxy)indene                                                                propranolol                                                                             4    BHR  250 ± 10                                                                         253 ± 17                                                                         251 ± 18                                                                         230 ± 10                                                                         225 ± 13                                                                         --                          (Inderal)      Res  100    79 ± 4                                                                           57 ± 4                                                                           38 ± 7                                                                           21 ± 3                                                                          --   0.063 ± 0.009       alprenolol                                                                              4    BHR  225 ± 12                                                                         233 ± 12                                                                         247 ± 11                                                                         261 ± 7                                                                          262 ± 4                                                                          --                          (Aptin)        Res  100    65 ± 3                                                                           44 ± 3                                                                           17 ± 3                                                                           3 ± 1                                                                           --   0.030 ±             __________________________________________________________________________                                                           0.003                   abbreviations;                                                                .sup.a) BHR: Basic heart rate (the heart rate just before administration      of l-isoproterenol, unit = beat per minute)                                   .sup.b) Res: Response (percent increase of heart rate induced by 0.1          μg/kg l-isoproterenol)                                                

EXAMPLE II

To a solution of 0.44 g. of 4-hydroxyindene in 4 ml. of an aqueous 10%potassium hydroxide solution there was added 0.65 g. of1-chloro-2-hydroxy-3-isopropylaminopropane. After stirring the resultingmixture at room temperature for 15 hours, the reaction mixture wasextracted with ether, the ether extract was dried with anhydrous sodiumcarbonate and the ether was distilled off under reduced pressure. Theresidue was subjected to silica gel column chromatography using acetoneas eluent, and 0.23 g. of white crystals of4-(3-isopropylamino-2-hydroxypropoxy)indene was obtained.

When the crystals obtained above were mixed with the4-(3-isopropylamino-≢2-hydroxypropoxy)indene obtained according to theprocess of Example 1, no lowering of melting point was observed.

                  Example III                                                     ______________________________________                                        Preparation of tablets.                                                       Prescription                                                                  4-(3-isopropylamino-2-hydroxy-                                                  propoxy)indene      0.2 g.                                                  Microcrystalline Cellulose                                                                          1.4 g.                                                  Starch                0.7 g.                                                  Talc                  0.2 g.                                                  ______________________________________                                    

This mixture was made into 20 tablets. The tablets were formed on a 7.0mm. deep cup punch. They may be coated according to conventional methodsif desired.

EXAMPLE IV

Preparation of injections.

In 100 ml. of saline solution there were dissolved 100 ml. of4-(3-isopropylamino-2-hydroxypropoxy)indene hydrochloride and thesolution thus formed was aseptically divided by 2 ml. into 50 ampouleseach containing 2 mg. of the active compound.

EXAMPLE V

To a solution of 1 g of 4-(2,3-epoxypropoxy)indene in 8 ml. of absoluteethanol was added 1.2 g. of sec-butylamine and the resulting solutionwas stirred at room temperature overnight. The reaction solution wasconcentrated under reduced pressure to give a yellow oily product, whichwas dissolved in 25 ml. of ether. To the resulting solution was addeddropwise hydrogen chloride in ether to form white precipitates. Theprecipitates thus formed were recovered by filtration and recrystallizedfrom isopropyl alcohol to provide 1.1 g. of the hydrochloride of4-(3-sec-butylamino-2-hydroxypropoxy)indene. M.P. 125°-126° C.

    ______________________________________                                        Elementary analysis as C.sub.16 H.sub.24 NO.sub.2 Cl                                   C (%)   H (%)    N (%)    Cl (%)                                     ______________________________________                                        Calculated:                                                                              64.53     8.12     4.70   11.90                                    Found:     64.30     8.12     4.83   11.72                                    ______________________________________                                    

EXAMPLE VI

To a solution of 1 g. of 4-(2,3-epoxypropoxy)indene in 6 ml. of absoluteethanol was added 1.6 g. of cyclohexylamine and the resulting solutionwas stirred at room temperature overnight. The solution thus obtainedwas concentrated under reduced pressure to give a yellow oily product,which was dissolved in 25 ml. of ether. To the resulting ether solutionwas added dropwise hydrogen chloride in ether to form whiteprecipitates. The precipitates were recovered by filtration andrecrystallized from isopropyl alcohol to provide 1.0 g. of thehydrochloride of 4-(3-cyclohexylamino-2-hydroxypropoxy)indene. M.P.168° - 169° C.

    ______________________________________                                        Elementary analysis as C.sub.18 H.sub.26 NO.sub.2 Cl:                                  C (%)   H (%)    N (%)    Cl (%)                                     ______________________________________                                        Calculated:                                                                              66.76     8.09     4.32   10.95                                    Found:     66.97     8.42     4.46   11.04                                    ______________________________________                                    

EXAMPLE VII

To a solution of 1 g. of 4-(2,3-epoxypropoxy)indene in 6 ml. of absoluteethanol was added 1.2 g. of tert-butylamine and the resulting solutionwas stirred at room temperature overnight. The resulting solution wasconcentrated under reduced pressure to give a yellow oily product, whichwas subjected to column chromatography using a column (having an insidediameter of 3.5 cm. and a height of 8 cm.) packed with silica gel. The9th to 14th fractions (volume of one fraction is 10 ml.) recovered fromthe chromatographic column using acetone as the effluent were combinedtogether and concentrated, and thereafter allowed to stand to formprecipitates. The precipitates were recrystallized from n-hexane toprovide 0.2 g. of white crystals of4-(3-tert-butylamino-2-hydroxypropoxy)indene. M.P. 84° - 85° C.

    ______________________________________                                        Elementary analysis as C.sub.16 H.sub.23 NO.sub.2 :                                      C (%)    H (%)    N (%)                                            ______________________________________                                        Calculated:  73.53     8.87      5.36                                         Found:       73.66     9.13      5.32                                         ______________________________________                                    

EXAMPLE VIII

To 5 ml. of isopropyl alcohol were added 0.4 g. of4-(2,3-epoxypropoxy)indene and 0.8 g. of β-phenylisopropylamine. Afterheating the resulting solution at 50° - 60° C. for 3 hours, isopropylalcohol was distilled off at the same temperature under reducedpressure, and by further heating, excess β-phenylisopropylamine wasdistilled off. The residue thus obtained was dissolved in 30 ml. ofn-hexane under heating, the insoluble materials were filtered and thefiltrate thus obtained was concentrated to obtain oily materials. Theoily materials were dissolved, in a small quantity of methanol and tothe resulting material was added 10% hydrochloric acid to provide 0.5 g.of 4-(3-β-phenylisopropylamino-2-hydroxypropoxy)indene hydrochloride.M.P. 203° - 205° C. (from methanol).

    ______________________________________                                        Elementary analysis as C.sub.21 H.sub.26 NO.sub.2 Cl:                                    C (%)   H (%)     N (%)                                            ______________________________________                                        Calculated:  70.08     7.28      3.89                                         Found:       70.19     7.19      4.14                                         ______________________________________                                    

EXAMPLE IX

Optical resolution of (±)-4-(3-isopropoxylamino-2-hydroxypropoxy)indene:

a. (-)-4-(3-isopropylamino-2-hydroxypropoxy)indene:

4.9 g. of (±)-4-(3-isopropylamino-2-hydroxypropoxy)indene and 7.5 g. of(-)-o,o-dibenzoyltartaric acid were dissolved in the mixture of 40 ml.of methanol and 20 ml. of water at 40°-50° C., and the resultingsolution was cooled gradually to room temperature to form 6 g. ofprecipitates. The precipitates were recovered by filtration andrecrystallized from 66 % methanol [methanol: water = 2:1 (volume)],until the rotation of crystals became constant. 0.6 g. of(-)-4-(3-isopropylamino-2-hydroxypropoxy)indene(-)-o,o-dibenzoyltartarate was obtained [α]_(D) ²¹ = -78.8 (c=1.0,ethanol).

To 0.4 g. of(-)-4-(3-isopropylamino-2-hydroxypropoxy)indene(-)-o,o-dibenzoyltartaratewere added 10 ml of 1 N hydrochloric acid and 20 ml of ether whilestirring, and the water layer was separated and washed with ether. Thewater layer was neutralized with 10 ml of 1 N sodium hydroxide andextracted with 30 ml of n-hexane. After the n-hexane extract was driedover anhydrous sodium carbonate, the n-hexane was distilled off toprovide 140 mg. of (-)-4-(3-isopropylamino-2-hydroxypropoxy)indene.[α]_(D) ²¹ = -9.3 (c=2.0, ethanol).

Hydrogen chloride was bubbled into the solution of 120 mg. of(-)-4-(3-isopropylamino-2-hydroxypropoxy)indene in ether to give 110 mg.of the hydrochloride of (-)-4-(3-isopropylamino-2-hydroxypropoxy)indene.

The compound thus obtained was recrystallized from methanol-ether[α]_(D) ²¹ = -25.2 (c=2.0, ethanol).

b. (+)-4-(3-isopropylamino-2-hydroxypropoxy)indene:

The filtrate obtained according to a above was concentrated underreduced pressure to provide an oily residue. When the oily residue isused in place of(-)-4-(3-isopropylamino-2-hydroxypropoxy)indene(-)-o,o-dibenzoyltartaratein the procedure of a, 1.2 g. of(+)-4-(3-isopropylamino-2-hydroxypropoxy)indene were obtained. [α]_(D)²¹ = +6.2 (c=1.0, ethanol).

To the solution of 1.2 g. of(+)-4-(3-isopropylamino-2-hydroxypropoxy)indene in 20 ml. of ether wasadded 10 ml. of ether containing 1.8 g. of (-)-o,o-dibenzoyltartaricacid to form an oily substance. The oily substance was recovered byfiltration, and recrystallized from methanol, until the rotation ofcrystals became constant. 0.5 g. of(+)-4-(3-isopropylamino-2-hydroxypropoxy)indene1/2(-)-o,o-dibenzoyltartarate was obtained. [α]_(D) ²¹ = -36.8 (c=1, 96%ethanol).

150 mg. of (+)-4-(3-isopropylamino-2-hydroxypropoxy)indene {[α]_(D) ²¹ =+8.8 (c=1, ethanol)} and 110 mg. of the hydrochloride of(+)-4-(3-isopropylamino-2-hydroxypropoxy)indene {[α]_(D) ²¹ = +24.1(c=1, ethanol)} were prepared by the method described in a by using(+)-4-(3-isopropylamino-2-hydroxypropoxy)indene.

What is claimed is:
 1. A compound selected from the group consisting of4-(3-isopropylamino-2-hydroxypropoxy)indene and a non-toxic acidaddition salt thereof.
 2. A compound as claimed in claim 1, which is(±)-4-(3-isopropylamino-2-hydroxypropoxy)indene or a non-toxic acidaddition salt thereof.
 3. A compound as claimed in claim 1, which is(+)-4-(3-isopropylamino-2-hydroxypropoxy)indene or a non-toxic acidaddition salt thereof.
 4. A compound as claimed in claim 1, which is(-)-4-(3-isopropylamino-2-hydroxypropoxy)indene or a non-toxic acidaddition salt thereof.